Potent inducers of terminal differentiation and methods of use thereof

ABSTRACT

The present invention provides the compound having the structure: ##STR1## wherein each of R 1  and R 2  are independently the same as or different from each other; when R 1  and R 2  are the same, each is a substituted or unsubstituted arylamino, cycloalkylamino, pyridineamino, piperidino, 9-purine-6-amine, or thiozoleamino group; when R 1  and R 2  are different, R 1  =R 3  --N--R 4 , wherein each of R 3  and R 4  are independently the same as or different from each other and are a hydrogen atom, a hydroxyl group, a substituted or unsubstituted, branched or unbranched alkyl, alkenyl, cycloalkyl, aryl, alkyloxy, aryloxy, arylalkyloxy, or pyridine group, or R 3  and R 4  bond together to form a piperidine group and R 2  is a hydroxylamino, hydroxyl, amino, alkylamino, dialkylamino or alkyloxy group; and n is an integer from about 4 to about 8. 
     The present invention also provides a method of selectively inducing terminal differentiation of neoplastic cells and thereby inhibiting proliferation of such cells. Moreover, the present invention provides a method of treating a patient having a tumor characterized by proliferation of neoplastic cells. Lastly, the present invention provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically acceptable amount of the compound above.

BACKGROUND OF THE INVENTION

Throughout this application various publications are referenced byarabic numerals within parentheses. Full citations for thesepublications may be found at the end of the specification immediatelypreceding the claims. The disclosures of these publications in theirentireties are hereby incorporated by reference into this application inorder to more fully describe the state of the art to which thisinvention pertains.

Cancer is a disorder in which a population of cells has become, invarying degrees, unresponsive to the control mechanisms which normallygovern proliferation and differentiation. For many years there have beentwo principal strategies for chemotherapeutic treatment of cancer: a)blocking hormone-dependent tumor cell proliferation by interference withthe production or peripheral action of sex hormones; and b) killingcancer cells directly by exposing them to cytotoxic substances, whichinjure both neoplastic and normal cell populations.

Relatively recently, cancer therapy is also being attempted by theinduction of terminal differentiation of the neoplastic cells (1). Incell culture models differentiation has been reported by exposure ofcells to a variety of stimuli, including: cyclic AMP and retinoic acid(2,3), aclarubicin and other anthracyclines (4).

There is abundant evidence that neoplastic transformation does notnecessarily destroy the potential of cancer cells to differentiate(1,5,6). There are many examples of tumor cells which do not respond tothe normal regulators of proliferation and appear to be blocked in theexpression of their differentiation program, and yet can be induced todifferentiate and cease replicating. A variety of agents, including somerelatively simple polar compounds (5,7-9), derivatives of vitamin D andretinoic acid (10-12), steroid hormones (13), growth factors (6,14),proteases (15,16), tumor promoters (17,18), and inhibitors of DNA or RNAsynthesis (4,19-24), can induce various transformed cell lines andprimary human tumor explants to express more differentiatedcharacteristics.

Early studies by the present inventors identified a series of polarcompounds that were effective inducers of differentiation in a number oftransformed cell lines (8,9). Of these, the most effective inducer, wasthe hybrid polar/apolar compound N,N'-hexamethylene bisacetamide (HMBA)(9). The use of this polar/apolar compound to induce murineerythroleukemia cells (MELC) to undergo erythroid differentiation withsuppression of oncogenicity has proved a useful model to studyinducer-mediated differentiation of transformed cells (5,7-9).HMBA-induced MELC terminal erythroid differentiation is a multistepprocess. Upon addition of HMBA to MELC (745A-DS19) in culture, there isa latent period of 10 to 12 hours before commitment to terminaldifferentiation is detected. Commitment is defined as the capacity ofcells to express terminal differentiation despite removal of inducer(25). Upon continued exposure to HMBA there is progressive recruitmentof cells to differentiate. The present inventors have reported that MELCcell lines made resistant to relatively low levels of vincristine becomemarkedly more sensitive to the inducing action of HMBA and can beinduced to differentiate with little or no latent period (26).

HMBA is capable of inducing phenotypic changes consistent withdifferentiation in a broad variety of cells lines (5). Thecharacteristics of the drug induced effect have been most extensivelystudied in the murine erythroleukemia cell system (MELC) (5,25,27,28).MELC induction of differentiation is both time and concentrationdependent. The minimum concentration required to demonstrate an effectin vitro in most strains is 2 to 3 mM; the minimum duration ofcontinuous exposure generally required to induce differentiation in asubstantial portion (>20%) of the population without continuing drugexposure is about 36 hours.

The primary target of action of HMBA is not known. There is evidencethat protein kinase C is involved in the pathway of inducer-mediateddifferentiation (29). The in vitro studies provided a basis forevaluating the potential of HMBA as a cytodifferentiation agent in thetreatment of human cancers (30). Several phase I clinical trials withHMBA have been completed (31-36). Clinical trials have shown that thiscompound can induce a therapeutic response in patients with cancer(35,36). However, these phase I clinical trials also have demonstratedthat the potential efficacy of HMBA is limited, in part, by dose-relatedtoxicity which prevents achieving optimal blood levels and by the needfor intravenous administration of large quantities of the agent, overprolonged periods.

Recently, the present inventors have reported a number of compoundsrelated to HMBA with polar groups separated by apolar linkages that, ona molar basis, are as active (37) or 100 times more active than HMBA(38). As a class, however, it has been found that the symmetrical dimerssuch as HMBA and related compounds are not the best cytodifferentiatingagents.

It has unexpectedly been found that the best compounds comprise twopolar end groups separated by a flexible chain of methylene groups,wherein one or both of the polar end groups is a large hydrophobicgroup. Preferably, the polar end groups are different and only one is alarge hydrophobic group. These compounds are unexpectedly a thousandtimes more active than HMBA and ten times more active than HMBA relatedcompounds.

This new class of compounds of the present invention may be useful forselectively inducing terminal differentiation of neoplastic cells andtherefore aid in treatment of tumors in patients.

SUMMARY OF THE INVENTION

The present invention provides the compound having the structure:##STR2## wherein each of R₁ and R₂ are independently the same as ordifferent from each other; when R₁ and R₂ are the same, each is asubstituted or unsubstituted arylamino, cycloalkylamino, pyridineamino,piperidino, 9-purine-6-amine, or thiozoleamino group; when R₁ and R₂ aredifferent, R₁ =R₃ --N--R₄, wherein each of R₃ and R₄ are independentlythe same as or different from each other and are a hydrogen atom, ahydroxyl group, a substituted or unsubstituted, branched or unbranchedalkyl, alkenyl, cycloalkyl, aryl, alkyloxy, aryloxy, arylalkyloxy, orpyridine group, or R₃ and R₄ bond together to form a piperidine groupand R₂ is a hydroxylamino, hydroxyl, amino, alkylamino, dialkylamino oralkyloxy group; and n is an integer from about 4 to about 8.

The present invention also provides the compound above having thestructure: ##STR3## wherein each of R₃ and R₄ are independently the sameas or different from each other and are a hydrogen atom, a hydroxylgroup, a substituted or unsubstituted, branched or unbranched alkyl,alkenyl, cycloalkyl, aryl, alkyloxy, aryloxy, arylalkyloxy, or pyridinegroup, or R₃ and R₄ bond together to form a piperidine group; R₂ is ahydroxylamino, hydroxyl, amino, alkylamino, dialkylamino or alkyloxygroup; and n is an integer from about 4 to about 8.

The present invention also provides the compound above having thestructure: ##STR4## wherein R is a substituted or unsubstitutedarylamino, cycloalkylamino, pyridineamino, piperidino, 9-purine-6-amine,or thiozoleamino group; and n is an integer from about 4 to about 8.

The present invention also provides the compound having the structure:##STR5## wherein each of X and Y are independently the same as ordifferent from each other and are a hydroxyl, amino or hydroxylaminogroup, a substituted or unsubstituted alkyloxy, alkylamino,dialkylamino, arylamino, alkylarylamino, alkyloxyamino, aryloxyamino,alkyloxyalkylamino, or aryloxyalkylamino group; R is a hydrogen atom, ahydroxyl group, a substituted or unsubstituted alkyl, aryl, alkyloxy, oraryloxy group; and each of m and n are independently the same as ordifferent from each other and are each an integer from about 0 to about8.

The present invention further provides the compound having thestructure: ##STR6## wherein each of X and Y are independently the sameas or different from each other and are a hydroxyl, amino orhydroxylamino group, a substituted or unsubstituted alkyloxy,alkylamino, dialkylamino, arylamino, alkylarylamino, alkyloxyamino,aryloxyamino, alkyloxyalkylamino, or aryloxyalkylamino group; each of R₁and R₂ are independently the same as or different from each other andare a hydrogen atom, a hydroxyl group, a substituted or unsubstitutedalkyl, aryl, alkyloxy, or aryloxy group; and each of m, n, and o areindependently the same as or different from each other and are each aninteger from about 0 to about 8.

The present invention still further provides the compound having thestructure: ##STR7## wherein each of X and Y are independently the sameas or different from each other and are a hydroxyl, amino orhydroxylamino group, a substituted or unsubstituted alkyloxy,alkylamino, dialkylamino, arylamino, alkylarylamino, alkyloxyamino,aryloxyamino, alkyloxyalkylamino, or aryloxyalkylamino group; each of R₁and R₂ are independently the same as or different from each other andare a hydrogen atom, a hydroxyl group, a substituted or unsubstitutedalkyl, aryl, alkyloxy, or aryloxy group; and each of m and n areindependently the same as or different from each other and are each aninteger from about 0 to about 8.

The present invention also provides the compound having the structure:##STR8## wherein each of X and Y are independently the same as ordifferent from each other and are a hydroxyl, amino or hydroxylaminogroup, a substituted or unsubstituted alkyloxy, alkylamino,dialkylamino, arylamino, alkylarylamino, alkyloxyamino, aryloxyamino,alkyloxyalkylamino, or aryloxyalkylamino group; and each of m and n areindependently the same as or different from each other and are each aninteger from about 0 to about 8.

The present invention also provides the compound having the structure:##STR9## wherein each of X and Y are independently the same as ordifferent from each other and are a hydroxyl, amino or hydroxylaminogroup, a substituted or unsubstituted alkyloxy, alkylamino,dialkylamino, arylamino, alkylarylamino, alkyloxyamino, aryloxyamino,alkyloxyalkylamino, or aryloxyalkylamino group; each of R₁ and R₂ areindependently the same as or different from each other and are ahydrogen atom, a hydroxyl group, a substituted or unsubstituted alkyl,aryl, alkyloxy, or aryloxy group; and each of m and n are independentlythe same as or different from each other and are each an integer fromabout 0 to about 8.

The present invention further provides the compound having thestructure: ##STR10## wherein each of X and Y are independently the sameas or different from each other and are a hydroxyl, amino orhydroxylamino group, a substituted or unsubstituted alkyloxy,alkylamino, dialkylamino, arylamino, alkylarylamino, alkyloxyamino,aryloxyamino, alkyloxyalkylamino, or aryloxyalkylamino group; and n isan integer from about 0 to about 8.

The present invention still further provides the compound having thestructure: ##STR11## wherein each of X and Y are independently the sameas or different from each other and are a hydroxyl, amino orhydroxylamino group, a substituted or unsubstituted alkyloxy,alkylamino, dialkylamino, arylamino, alkylarylamino, alkyloxyamino,aryloxyamino, alkyloxyalkylamino, or aryloxyalkylamino group; each of R₁and R₂ are independently the same as or different from each other andare a hydrogen atom, a hydroxyl group, a substituted or unsubstitutedalkyl, aryl, alkyloxy, aryloxy, carbonylhydroxylamino, or fluoro group;and each of m and n are independently the same as or different from eachother and are each an integer from about 0 to about 8.

The present invention also provides the compound having the structure:##STR12## wherein each of R₁ and R₂ are independently the same as ordifferent from each other and are a hydroxyl, alkyloxy, amino,hydroxylamino, alkylamino, dialkylamino, arylamino, alkylarylamino,alkyloxyamino, aryloxyamino, alkyloxyalkylamino, or aryloxyalkylaminogroup.

The present invention also provides the compound having the structure:##STR13## wherein each of R₁ and R₂ are independently the same as ordifferent from each other and are a hydroxyl, alkyloxy, amino,hydroxylamino, alkylamino, dialkylamino, arylamino, alkylarylamino,alkyloxyamino, aryloxyamino, alkyloxyalkylamino, or aryloxyalkylaminogroup.

The present invention further provides the compound having thestructure: ##STR14## wherein each of R₁ and R₂ are independently thesame as or different from each other and are a hydroxyl, alkyloxy,amino, hydroxylamino, alkylamino, dialkylamino, arylamino,alkylarylamino, alkyloxyamino, aryloxyamino, alkyloxyalkylamino, oraryloxyalkylamino group.

In addition, the present invention provides a method of selectivelyinducing terminal differentiation of neoplastic cells and therebyinhibiting proliferation of such cells which comprises contacting thecells under suitable conditions with an effective amount of any of thecompounds above, effective to selectively induce terminaldifferentiation.

The present invention also provides a method of treating a patienthaving a tumor characterized by proliferation of neoplastic cells whichcomprises administering to the patient an effective amount of any of thecompounds above, effective to selectively induce terminaldifferentiation of such neoplastic cells and thereby inhibit theirproliferation.

Lastly, the present invention provides a pharmaceutical compositioncomprising a pharmaceutically acceptable carrier and a therapeuticallyacceptable amount of any of the compounds above.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides the compound having the structure:##STR15## wherein each of R₁ and R₂ are independently the same as ordifferent from each other; when R₁ and R₂ are the same, each is asubstituted or unsubstituted arylamino, cycloalkylamino, pyridineamino,piperidino, 9-purine-6-amine, or thiozoleamino group; when R₁ and R₂ aredifferent, R₁ =R₃ --N--R₄, wherein each of R₃ and R₄ are independentlythe same as or different from each other and are a hydrogen atom, ahydroxyl group, a substituted or unsubstituted, branched or unbranchedalkyl, alkenyl, cycloalkyl, aryl, alkyloxy, aryloxy, arylalkyloxy, orpyridino group, or R₃ and R₄ bond together to form a piperidine groupand R₂ is a hydroxylamino, hydroxyl, amino, alkylamino, dialkylamino oralkyloxy group; and n is an integer from about 4 to about 8.

The present invention also provides the compound above having thestructure: ##STR16## wherein each of R₃ and R₄ are independently thesame as or different from each other and are a hydrogen atom, a hydroxylgroup, a substituted or unsubstituted, branched or unbranched alkyl,alkenyl, cycloalkyl, aryl, alkyloxy, aryloxy, arylalkyloxy, or pyridinegroup, or R₃ and R₄ bond together to form a piperidine group; R₂ is ahydroxylamino, hydroxyl, amino, alkylamino, dialkylamino or alkyloxygroup; and n is an integer from about 4 to about 8.

In the preferred embodiment of the compound above, R₂ is ahydroxylamino, hydroxyl, amino, methylamino, dimethylamino, or methyoxygroup and n is 6. Most preferably, R₄ is a hydrogen atom and R₃ is asubstituted or unsubstituted phenyl group.

The phenyl group may be substituted with a methyl, cyano, nitro,trifluoromethyl, amino, aminocarbonyl, methylcyano, chloro, fluoro,bromo, iodo, 2,3-difluoro, 2,4-difluoro, 2,5-difluoro, 3,4-difluoro,3,5-difluoro, 2,6-difluoro, 1,2,3-trifluoro, 2,3,6-trifluoro,2,4,6-trifluoro, 3,4,5-trifluoro, 2,3,5,6-tetrafluoro,2,3,4,5,6-pentafluoro, azido, hexyl, t-butyl, phenyl, carboxyl,hydroxyl, methyoxy, benzyloxy, phenylaminooxy, phenylmethoxy,phenylaminocarbonyl, methyoxycarbonyl, methylaminocarbonyl,dimethylamino, dimethylaminocarbonyl, or hydroxylaminocarbonyl group.

In other preferred embodiments of the compound above, R₄ is a hydrogenatom and R₃ is a cyclohexyl group; R₄ is a hydrogen atom and R₃ is amethyoxy group; R₃ and R₄ each bond together to form a piperidine group;R₄ is a hydrogen atom and R₃ is a hydroxyl group; R₄ is a hydrogen atomand R₃ is a benzyloxy group; R₄ is a hydrogen atom and R₃ is aδ-pyridine group; R₄ is a hydrogen atom and R₃ is a β-pyridine group; R₄is a hydrogen atom and R₃ is a α-pyridine group; R₃ and R₄ are bothmethyl groups; or R₄ is a methyl group and R₃ is a phenyl group.

The present invention also provides the compound having the structure:##STR17## wherein R is a substituted or unsubstituted arylamino,cycloalkylamino, pyridineamino, piperidino, 9-purine-6-amine, orthiozoleamino group; and n is an integer from about 4 to about 8.

In the preferred embodiment of the compound above, R is a substituted orunsubstituted phenylamino group. The phenylamino group may besubstituted with a cyano, methylcyano, nitro, carboxyl, aminocarbonyl,methylaminocarbonyl, dimethylaminocarbonyl, trifluoromethyl,hydroxylaminocarbonyl, N-hydroxylaminocarbonyl, methoxycarbonyl, chloro,fluoro, methyl, methoxy, 2,3-difluoro, 2,3-difluoro, 2,4-difluoro,2,5-difluoro, 2,6-difluoro, 3,5-difluoro, 2,6-difluoro, 2,3,6-trifluoro,1,2,3-trifluoro, 3,4,5-trifluoro, 2,3,4,5-tetrafluoro, or2,3,4,5,6-pentafluoro group.

In another embodiment of the compound above, R is a cyclohexylaminogroup.

The present invention also provides the compound having the structure:##STR18## wherein each of X and Y are independently the same as ordifferent from each other and are a hydroxyl, amino or hydroxylaminogroup, a substituted or unsubstituted alkyloxy, alkylamino,dialkylamino, arylamino, alkylarylamino, alkyloxyamino, aryloxyamino,alkyloxyalkylamino, or aryloxyalkylamino group; R is a hydrogen atom, ahydroxyl group, a substituted or unsubstituted alkyl, aryl, alkyloxy, oraryloxy-group; and each of m and n are independently the same as ordifferent from each other and are each an integer from about 0 to about8.

In the preferred embodiment of the compound above, each of X, Y, and Ris a hydroxyl group and each of m and n is 5.

The present invention also provides the compound having the structure:##STR19## wherein each of X and Y are independently the same as ordifferent from each other and are a hydroxyl, amino or hydroxylaminogroup, a substituted or unsubstituted alkyloxy, alkylamino,dialkylamino, arylamino, alkylarylamino, alkyloxyamino, aryloxyamino,alkyloxyalkylamino, or aryloxyalkylamino group; each of R₁ and R₂ areindependently the same as or different from each other and are ahydrogen atom, a hydroxyl group, a substituted or unsubstituted alkyl,aryl, alkyloxy, or aryloxy group; and each of m, n, and o areindependently the same as or different from each other and are each aninteger from about 0 to about 8.

In the preferred embodiment of the compound above, each of X and Y is ahydroxyl group and each of R₁ and R₂ is a methyl group. Most preferably,each of n and o is 6, and m is 2.

The present invention also provides the compound having the structure:##STR20## wherein each of X and Y are independently the same as ordifferent from each other and are a hydroxyl, amino or hydroxylaminogroup, a substituted or unsubstituted alkyloxy, alkylamino,dialkylamino, arylamino, alkylarylamino, alkyloxyamino, aryloxyamino,alkyloxyalkylamino, or aryloxyalkylamino group; each of R₁ and R₂ areindependently the same as or different from each other and are ahydrogen atom, a hydroxyl group, a substituted or unsubstituted alkyl,aryl, alkyloxy, or aryloxy group; and each of m and n are independentlythe same as or different from each other and are each an integer fromabout 0 to about 8.

The present invention also provides the compound having the structure:##STR21## wherein each of X and Y are independently the same as ordifferent from each other and are a hydroxyl, amino or hydroxylaminogroup, a substituted or unsubstituted alkyloxy, alkylamino,dialkylamino, arylamino, alkylarylamino, alkyloxyamino, aryloxyamino,alkyloxyalkylamino, or aryloxyalkylamino group; and each of m and n areindependently the same as or different from each other and are each aninteger from about 0 to about 8.

In the preferred embodiment of the compound above, each of X and Y is ahydroxyl group and each of m and n is 5.

The present invention also provides the compound having the structure:##STR22## wherein each of X and Y are independently the same as ordifferent from each other and are a hydroxyl, amino or hydroxylaminogroup, a substituted or unsubstituted alkyloxy, alkylamino,dialkylamino, arylamino, alkylarylamino, alkyloxyamino, aryloxyamino,alkyloxyalkylamino, or aryloxyalkylamino group; each of R₁ and R₂ areindependently the same as or different from each other and are ahydrogen atom, a hydroxyl group, a substituted or unsubstituted alkyl,aryl, alkyloxy, or aryloxy group; and each of m and n are independentlythe same as or different from each other and are each an integer fromabout 0 to about 8.

The present invention also provides the compound having the structure:##STR23## wherein each of X and Y are independently the same as ordifferent from each other and are a hydroxyl, amino or hydroxylaminogroup, a substituted or unsubstituted alkyloxy, alkylamino,dialkylamino, arylamino, alkylarylamino, alkyloxyamino, aryloxyamino,alkyloxyalkylamino, or aryloxyalkylamino group; and n is an integer fromabout 0 to about 8.

In the preferred embodiment of the compound above, each of X and Y is adimethylamino group and n is 4 or 5.

The present invention also provides the compound having the structure:##STR24## wherein each of X and Y are independently the same as ordifferent from each other and are a hydroxyl, amino or hydroxylaminogroup, a substituted or unsubstituted alkyloxy, alkylamino,dialkylamino, arylamino, alkylarylamino, alkyloxyamino, aryloxyamino,alkyloxyalkylamino, or aryloxyalkylamino group; each of R₁ and R₂ areindependently the same as or different from each other and are ahydrogen atom, a hydroxyl group, a substituted or unsubstituted alkyl,aryl, alkyloxy, aryloxy, carbonylhydroxylamino, or fluoro group; andeach of m and n are independently the same as or different from eachother and are each an integer from about 0 to about 8.

In the preferred embodiment of the compound above, each of X and Y is ahydroxylamino group, R₁ is a methyl group, R₂ is a hydrogen atom, andeach of m and n is 2. In another preferred embodiment, each of X and Yis a hydroxylamino group, R₁ is a carbonylhydroxylamino group, R₂ is ahydrogen atom, and each of m and n is 5. In a further preferredembodiment, each of X and Y is a hydroxylamino group, each of R₁ and R₂is a fluoro group, and each of m and n is 2.

The present invention also provides the compound having the structure:##STR25## wherein each of R₁ and R₂ are independently the same as ordifferent from each other and are a hydroxyl, alkyloxy, amino,hydroxylamino, alkylamino, dialkylamino, arylamino, alkylarylamino,alkyloxyamino, aryloxyamino, alkyloxyalkylamino, or aryloxyalkylaminogroup.

Preferably, R₁ is a phenylamino group and R₂ is a hydroxylamino group.

The present invention also provides the compound having the structure:##STR26## wherein each of R₁ and R₂ are independently the same as ordifferent from each other and are a hydroxyl, alkyloxy, amino,hydroxylamino, alkylamino, dialkylamino, arylamino, alkylarylamino,alkyloxyamino, aryloxyamino, alkyloxyalkylamino, or aryloxyalkylaminogroup.

Preferably, R₁ is phenylamino group and R₂ is hydroxylamino group.

The present invention also provides the compound having the structure:##STR27## wherein each of R₁ and R₂ are independently the same as ordifferent from each other and are a hydroxyl, alkyloxy, amino,hydroxylamino, alkylamino, dialkylamino, arylamino, alkylarylamino,alkyloxyamino, aryloxyamino, alkyloxyalkylamino, or aryloxyalkylaminogroup.

In the preferred embodiment, either R₁ or R₂ is a hydroxylamino group.

The present invention also provides a method of selectively inducingterminal differentiation of neoplastic cells and thereby inhibitingproliferation of such cells which comprises contacting the cells undersuitable conditions with an effective amount of any of the compoundsabove, effective to selectively induce terminal differentiation.

The contacting must be performed continuously for a prolonged period oftime, i.e. for at least 48 hours, preferably for about 4-5 days orlonger.

The method may be practiced in vivo or in vitro. If the method ispracticed in vitro, contacting may be effected by incubating the cellswith the compound. The concentration of the compound in contact with thecells should be from about 1 μM to about 25 mM, preferably from 4 μM toabout 5 mM. The concentration depends upon the individual compound andthe state of the neoplastic cells.

The method may also comprise initially treating the cells with anantitumor agent so as to render them resistant to an antitumor agent andsubsequently contacting the resulting resistant cells under suitableconditions with an effective amount of any of the compounds above,effective to selectively induce terminal differentiation of such cells.

The antitumor agent may be one of numerous chemotherapy agents such asan alkylating agent, an antimetabolite, a hormonal agent, an antibiotic,colchicine, a vinca alkaloid, L-asparaginase, procarbazine, hydroxyurea,mitotane, nitrosoureas or an imidazole carboxamide. Suitable agents arethose agents which promote depolarization of tubulin. Preferably theantitumor agent is colchicine or a vinca alkaloid; especially preferredare vinblastine and vincristine. In embodiments where the antitumoragent is vincristine, the cells preferably are treated so that they areresistant to vincristine at a concentration of about 5 mg/ml. Thetreating of the cells to render them resistant to an antitumor agent maybe effected by contacting the cells with the agent for a period of atleast 3-5 days. The contacting of the resulting cells with any of thecompounds above is performed as described previously.

The present invention also provides a method of treating a patienthaving a tumor characterized by proliferation of neoplastic cells whichcomprises administering to the patient an effective amount of any of thecompounds above, effective to selectively induce terminaldifferentiation of such neoplastic cells and thereby inhibit theirproliferation.

The method of the present invention is intended for the treatment ofhuman patients with tumors. However, it is also likely that the methodwould be effective in the treatment of tumors in other mammals. The termtumor is intended to include any cancer caused by the proliferation ofneoplastic cells, such as lung cancer, acute lymphoid myeloma, bladdermelanoma, renal carcinoma, breast carcinoma, or colorectal carcinoma.The administration of the compound to the patient may be effected orallyor parenterally. To date, administration intravenously has proven to beeffective. The administration of the compound must be performedcontinuously for a prolonged period of time, such as for at least 3 daysand preferably more than 5 days. In the most preferred embodiments, theadministration is effected continuously for at least 10 days and isrepeated at intervals wherein at each interval the administration iscontinuously effected for at least 10 days. For example, theadministration may be effected at intervals as short as 5-10 days, up toabout 25-35 days and continuously for at least 10 days during each suchinterval. The optimal interval period will vary depending on the type ofpatient and tumor. For example, in the incidence of acute leukemia, theso called myelodysplastic syndrome, continuous infusion would seem to beindicated so long as the patient tolerated the drug without toxicity andthere was a positive response.

The amount of the compound administered to the patient is less than anamount which would cause toxicity in the patient. In the certainembodiments, the amount of the compound which is administered to thepatient is less than the amount which causes a concentration of thecompound in the patient's plasma to equal or exceed the toxic level ofthe compound. Preferably, the concentration of the compound in thepatient's plasma is maintained at about 1.0 mM. It has been found withHMBA that administration of the compound in an amount from about 5 gm/m²/day to about 30 gm/m² /day, particularly about 20 gm/m² /day, iseffective without producing toxicity in the patient. The optimal amountof the compound which should be administered to the patient in thepractice of the present invention will depend on the particular compoundused and the type of cancer being treated.

This invention, in addition to the above listed compounds, is intendedto encompass the use of homologs and analogs of such compounds. In thiscontext, homologs are molecules having substantial structuralsimilarities to the above-described compounds and analogs are moleculeshaving substantial biological similarities regardless of structuralsimilarities.

The method may also comprise initially administering to the patient anamount of an antitumor agent to render the cells resistant to anantitumor agent and subsequently administering to the patient aneffective amount of any of the compounds above, effective to selectivelyinduce terminal differentiation of such neoplastic cells and therebyinhibit their proliferation.

The antitumor agent may be one of numerous chemotherapy agents such asan alkylating agent, an antimetabolite, a hormonal agent, an antibiotic,colchicine, a vinca alkaloid, L-asparaginase, procarbazine, hydroxyurea,mitotane, nitrosoureas or an imidazole carboxamide. Suitable agents arethose agents which promote depolarization of tubulin. Preferably theantitumor agent is colchicine or a vinca alkaloid; especially preferredare vinblastine and vincristine. In embodiments where the antitumoragent is vincristine, an amount is administered to render the cells areresistant to vincristine at a concentration of about 5 mg/ml. Theadministration of the agent is performed essentially as described abovefor the administration of any of the compounds. Preferably, theadministration of the agent is for a period of at least 3-5 days. Theadministration of any of the compounds above is performed as describedpreviously.

The present invention also provides a pharmaceutical compositioncomprising a pharmaceutically acceptable carrier, such as sterilepyrogen-free water, and a therapeutically acceptable amount of any ofthe compounds above. Preferably, the effective amount is an amounteffective to selectively induce terminal differentiation of suitableneoplastic cells and less than an amount which causes toxicity in apatient.

Lastly, the present invention provides the pharmaceutical compositionabove in combination with an antitumor agent. The antitumor agent may beany of the agents previously described.

The invention is illustrated in the Experimental Details section whichfollows. This section is set forth to aid in an understanding of theinvention but is not intended to, and should not be construed to, limitin any way the invention as set forth in the claims which followthereafter.

Experimental Details Cells and Materials

MELC 745A-DS19 cells and the variants of MELC derived from this cellline, namely, the vincristine-resistant MELC V3.17 and VCR.C(2)15 celllines (26), and the dimethylsulfoxide-resistant cell line, DR10 (39),were maintained in alpha minimal essential medium containing 10% fetalcalf serum (16). Cell cultures for all experiments were initiated withcells in logarithmic growth phase (day 2 cultured cells) at a density of10⁵ cells/ml. Inducer compounds were added in the final concentrationsindicated below, dissolved in culture medium without fetal calf serumunless otherwise indicated. Cell density and benzidine reactively weredetermined as described (16).

Commitment to terminal differentiation, characterized by limited celldivision (colony size<32 cells) and accumulation of hemoglobin(benzidine reactive colonies) was assayed by a colony cloning assayusing 2% methylcellulose as described (25) (see Table 1 for results).HL-60 human leukemia cells, derived from peripheral blood leukocytes ofa patient with acute promyelocytic leukemia (40). Induceddifferentiation of HL-60 cells assayed by determining the proportion ofcells that developed the capacity to reduce nitroblue tetrazolium (NBT)(41) (see Table 2 for results).

Chemistry

The compounds having the structure: ##STR28## Preparation of PhCH₂ONHOC(CH₂)₆ COOCH₃ :

A solution of suberic acid monomethyl ester (1.9 g; 0.01 mol), oxaloylchloride (1.75 mL; 2.54 g; 0.02 mol) and 0.1 mL DMF in benzene (200 mL)was stirred overnight at room temperature. The solvent was evaporatedand oily residue was dissolved in chloroform (.sup.˜ 20 mL) and mixedtogether with chloroform solution (100 mL) of O-benzylhydroxylamine(2.46 g; 0.02 mol) and pyridine (1.6 mL; 1.68 g; 0.02 mol). The reactionmixture was stirred at room temperature overnight. The chloroformsolution was washed with water (50 mL), 10% hydrochloric acid, and againwith water (2×50 mL). The organic layer was dried over anhydrousmagnesium sulfate and evaporated. The solid residue was slurried inhexanes (.sup.˜ 100 mL) and filtered. The yield of PhCH₂ ONHOC(CH₂)₆COOCH₃ was 2.61 g (89%). ##STR29##

The above suberic acid monobenzyloxyamide monomethyl ester (1 g; 3.4mol) was dissolved in dry methanol (50 mL) and 5% Pd-C (50 mg) wasadded. The black suspension was shaken under hydrogen pressure (.sup.˜50 psi) overnight at room temperature. The catalyst was separated byfiltration, and filtrate was evaporated. The solid residue was slurriedin hexanes (.sup.˜ 20 mL) and filtered. The yield of the monomethylester monohydroxamic acid of suberic acid was 900 mg (95%). ¹ H NMR(DMSO-d₆, 200 MHz), δ(ppm) 10.31 (s, NHOH, 1H); 8.89 (s, broad, NHOH,1H); 3.57 (s, CH₃, 3H); 2.27 (t, J=7.4 Hz, CH₂ COOCH₃, 2H); 1.91 (t,J=7.4 Hz, CH₂ CONHOH, 2H); 1.49 (m, 4H), 1.24(m, 4H). ##STR30##

Suberic acid monobenzyloxyamide monomethyl ester (1 g; 3.4 mmol) andpotassium hydroxide (210 mg; 3.75 mmol) were dissolved in 10 mL ofmethanol-water (4:1) mixture. The reaction mixture was refluxed twohours and solvent was evaporated. The solid residue was dissolved in 5mL water and acidified with conc. hydrochloric acid to pH.sup.˜ 5. Whiteprecipitate was filtered, dried and crystallized from ethylacetate-hexanes. The yield of suberic acid monobenzyloxyamide was 820 mg(86%). The product was dissolved in methanol (50 mL) and 5% Pd-C (50 mg)was added. The reaction mixture was shaken under hydrogen pressure (50psi) overnight. The catalyst was separated by filtration and filtratewas evaporated. The solid residue was slurried in hexanes and filtered.The yield of suberic acid monohydroxamic acid was 520 mg (81%). ¹ H NMR(DMSO-d₆, 200 MHz), δ(ppm) 11.96 (s, broad, COOH, 1H); 10.31 (s, NHOH,1H); 8.63 (s, broad, NHOH, 1H); 2.17 (s, J=7.4 Hz, CH₂ COOH, 2H); 1.91(s, CH₂ CONHOH, 2H); 1.46 (m, 4H); 1.22 (m, 4H).

Compounds having the structure: ##STR31##

General Procedure

A pyridine (500 mL) solution of O-benzylhydroxylamine (2.46 g; 0.02mol), the corresponding amine (0.02 mol) and suberoyl chloride wasstirred at room temperature overnight. The solvent was evaporated andthe semisolid residue was dissolved in 1000 mL chloroform-methanol(4:1); the resulting solution was washed with water (2×100 mL), 10%hydrochloric acid (3×100 mL), and again with water (2×100 mL). Organiclayer was dried over anhydrous magnesium sulfate and evaporated. Thesolid residue was dissolved in methanol (100 mL) and 5% Pd-C was added.The black suspension was shaken under hydrogen pressure (.sup.˜ 50 psi)overnight. The catalyst was separated by filtration, and the filtratewas evaporated. The target products were isolated by columnchromatography on silica gel with ethyl acetate-tetrahydrofuran.##STR32##

Yield 1.1 g (26%). ¹ H NMR (DMSO-D₆, 200 MHz), δ(ppm) 10.93 (s, NHOCH₃,1H); 10.32 (s, NHOH, 1H); 8.66 (s, NHOH, 1H); 3.55 (s, CH₃, 3H); 1.91(t, J=7.6 Hz, CH₂ CO--,4H); 1.45 (m, 4H); 1.20 (m, 4H). ##STR33##

Yield 1.2 g (21%). ¹ H NMR (DMSO-d₆, 200 MHz), δ(ppm) 10.31 (s, NHOH,1H); 8.60 (s, broad, NHOH, 1H); 7.57 (d, J=7.6 Hz, NH--C₆ H₁₁, 1H), 3.40(m, CH--NH, 1H); 1.99 (t, J=7 Hz, CH₂ CONHC₆ H₁₁, 2H); 1.91 (t, J=7.6Hz, CH₂ CONHOH, 2H); 1.63 (m, 4H); 1.44 (m, 6H); 1.20 (m, 8H). ##STR34##

Yield 870 mg (20%). ¹ H NMR (DMSO-D₆, 200 MHz), δ(ppm) 10.31 (s, NHOH,1H); 8.67 (s, broad, NHOH, 1H); 2.85 (d, J=30 Hz, N(CH₃)₂, 6H); 2.24 (t,J=7.4 Hz, CH₂ CON(CH₃), 2H); 1.91 (t, J=7.4 Hz, CH₂ COONHOH, 2H); 1.50(m, 4H); 1.20 (m, 4H). ##STR35##

Yield 1.4 g (27%); ¹ H NMR (DMSO-d₆, 200 MHz), δ(ppm) 10.31 (s, NHOH,1H); 8.67 (s, NHOH, 1H); 3.40 (2t, CH₂ N, 4H); 2.20 (t, J=7.4 Hz, CH₂CON(CH₂)₅, 2H); 1.91 (t, J=7.4 Hz, CH₂ CONHOH, 2H); 1.10-1.60 (m, broad,14H).

Compound having structure: ##STR36##

The chloroform (500 mL) solution of O-benzylhydroxylamine (1.23 g; 0.01mol), O-(trimethylsilyl)hydroxylamine (1.1 g; 0.01 mol), pyridine (1.6mL; 1.7 g; 0.02 mol) and suberoyl chloride (1.8 mL; 2.11 g; 0.01 mol)was stirred at room temperature overnight. The reaction suspension wasdiluted with methanol (100 mL), washed with 10% hydrochloric acid (3×100mL). The organic layer was dried over anhydrous magnesium sulfate andevaporated. The solid residue was subjected to chromatography on silicagel in ethyl acetate-tetrahydrofuran (4:1). The yield was 500 mg (17%).¹ H NMR (DMSO-d₆, 200 MHz), δ(ppm) 11.09 (s, NHOCH₂ C₆ H₅, 1H); 10.31(s, NHOH, 1H); 8.67 (s, broad, NHOH, 1H); 7.36 (s, C₆ H₅, 5H), 4.76 (s,CH₂ C₆ H₅, 2H); 1.92 (t, J=7.4 Hz, CH₂ CO--, 4H); 1.45 (m, 4H); 1.20 (m,4H).

Compound having the structure: ##STR37##

Into a cooled solution of potassium hydroxide (2.24 g; 0.04 mol) andO-benzylhydroxylamine hydrochloride in 30 mL of tetrahydrofuran-water(1:1) mixture, 6-bromohexanoyl chloride (3.1 mL; 4.27 g; 0.02 mol) wasadded. The reaction mixture was stirred at room temperature for onehour. The solvent was evaporated and solid residue was partitionedbetween chloroform (200 mL) and water (100 mL). Chloroform layer waswashed with 10% hydrochloric acid (3×50 mL) and water (2×50 mL). Theorganic layer was dried over anhydrous magnesium sulfate and evaporated.The product was purified by crystallization from ethyl acetate-hexanes.The yield of N-benzyloxy-6-bromohexanoyl amide was 4.7 g (78%). Adimethylsulfoxide (250 mL) solution of N-benzyloxy-6-bromohexanoyl amide(4.5 g; 15 mmol) and sodium cyanide (7.35 g; 0.15 mol) was heated at130° C. overnight. The solvent was evaporated and solid residue waspartitioned between chloroform (300 mL) and water (300 mL). Thechloroform layer was washed with water (5×100 mL), dried over anhydrousmagnesium sulfate, and evaporated. The oily residue was purified bycolumn chromatography on silica gel in ethyl acetate-tetrahydrofuran(4:1) as an eluent. The yield of N-benzyloxy-6-cyanohexanoylamide was1.62 g (43%). The product was dissolved in methanol (50 mL) and 5% Pd-C(100 mg) was added. The black suspension was shaken under hydrogenpressure (.sup.˜ 50 psi) overnight. The catalyst was isolated byfiltration and filtrate was evaporated. The solid residue was slurriedin hexanes (.sup.˜ 20 mL) and filtered. The yield ofN-hydroxy-6-cyanohexanoylamide was 900 mg (overall yield 30%). ¹ H NMR(DMSO-d₆, 200 MHz), δ(ppm) 10.32 (s, NHOH, 1H); 8.65 (s, NHOH, 1H); 2.45(t,J=7 Hz, CH₂ CN, 2H) 1.93 (t, J=7 Hz, CH₂ CONHOH, 2H); 1.49 (m, 4H);1.33 (m, 2H).

Compounds having the structure: ##STR38##

General Procedure

A diacid dichloride (0.01 mol) was added into a cooled (0° C.) solutionof potassium hydroxide (1.12 g; 0.02 mol) and corresponding amine (0.01mol) in 30 mL of tetrahydrofuran-water (1:1) mixture. The reactionmixture was stirred at room temperature about one hour. Solvent wasevaporated and the solid residue was partitioned between chloroform (300mL) and water (300 mL). In some cases a small amount of methanol isnecessary to dissolve all solid. The organic layer was washed with 10%potassium hydroxide (3×30 mL). The basic water extract was acidifiedwith 10% hydrochloric acid. The precipitate was collected by filtration,dried and purified by crystallization from ethyl acetate or by columnchromatography on silica gel in ethyl acetate-tetrahydrofuran (4:1). Theyields are from 20-37%. ##STR39##

¹ H NMR (DMSO-d₆, 200 MHz), δ(ppm) 11.97 (s, COOH, 1H); 9.84 (s, NH,1H); 7.57 (d, J=7.4 Hz, ortho aromatic protons, 2H); 7.26 (t, J=8.4 Hz,meta aromatic protons, 2H); 6.99 (t, J=7.4 Hz, para aromatic proton,1H), 2.27 (t, J=7 Hz, CH₂ CONHPh, 2H); 2.18 (t, J=7.2 Hz, 2H); 1.52 (m,4H); 1.28 (m, 4H). ##STR40##

¹ H NMR (DMSO-d₆, 200 MHz), δ(ppm) 11.95 (s, COOH, 1H); 10.20 (s, NH,1H); 8.10 (s, aromatic proton, 1H); 7.75 (m, aromatic proton, 1H); 7.45(m, aromatic proton, 2H); 2.28 (t, J=7.4 Hz, CH₂ CONHAr, 2H); 2.21 (t,J=7.2 Hz, CH₂ COOH, 2H); 1.46 (m, 4H); 1.20 (m, 4H). ##STR41##

¹ H NMR (DMSO-d₆, 200 MHz), δ(ppm) 11.95 (s, COOH, 1H); 10.29 (s, NH,1H); 7.75 (s, aromatic protons, 4H); 2.33 (t, J=7.2 Hz, CH₂ CONHAr, 2H);2.18 (t, J=7.4 Hz, CH₂ COOH, 2H); 1.53 (m, 4H); 1.27 (m, 4H). ##STR42##

¹ H NMR (DMSO-d₆, 200MHz), 11.98 (s, broad, COOH, 1H); 10.48 (s, NH,1H); 8.21 (d, J=9.2 Hz, aromatic protons, 2H); 7.82 (d, J=9.2 Hz,aromatic proton, 2H); 2.36 (t, J=7.4 Hz, CH₂ CONHAr, 2H); 2.18 (t, J=7.2Hz, CH₂ COOH, 2H); 1.55 (m, 4H); 1.29 (m, 4H). ##STR43##

¹ H NMR (DMSO-d₆, 200 MHz), δ(ppm) 12.00 (s, broad COOH, 1H); 10.24 (s,NH, 1H); 8.38 (d, J=5.8 Hz, aromatic protons, 2H); 7.55 (d, J=5.8 Hz,aromatic protons, 2H); 2.33 (t, J=7.2 Hz, CH₂ CONHAr, 2H); 2.18 (t,J=7.2 Hz, CH₂ COOH); 1.52 (m, 4H); 1.27 (m, 4H). ##STR44##

¹ H NMR (DMSO-d₆, 200 MHz), δ(ppm) 11.95 (s, COOH, 1H); 7.58 (d, J=8Hz); 3.50 (m, CH, 1H); 2.17 (t, J=7.2 Hz, CH₂ COOH, 2H); 2.00 (t, J=7Hz, CH₂ CONH--, 2H); 1.60 (m, 4H); 1.46 (m, 6H); 1.20 (m, 8H).

In the same way the following compounds were prepared and characterized:##STR45## wherein n=4, 5, 6, 7, and 8; R is hydrogen; 2-, 3-, and4-cyano; 2-, 3-, and 4-nitro; 2-, 3-, and 4-methylcyano; 2-, 3-, and4-trifluoromethyl; 2-, 3-, and 4-fluoro; ##STR46## wherein n=4, 5, 6, 7,and 8; ##STR47## wherein n=4, 5, 6, 7, and 8; ##STR48## wherein n=4, 5,6, 7, and 8; ##STR49## wherein n=4, 5, 6, 7, and 8; ##STR50## whereinn=4, 5, 6, 7, and 8; ##STR51## wherein R is 2-, 3-, and 4-carboxy; 2-,3-, and 4-aminocarbonyl; 2-, 3-, and 4-methylaminocarbonyl; 2-, 3-, and4-dimethylaminocarbonyl; 2-, 3-, and 4-chloro; 2-, 3-, and 4-bromo; 2-,3-, and 4-iodo; 2-, 3, and 4-methyl; 2-, 3-, and 4 methoxy; 2-, 3-, and4-hydroxy; 2-, 3-, and 4-amino; and 2-, 3-, and 4-dimethylamino.

Compounds having the general structure: ##STR52## wherein n=4, 5, 6, and7.

General Procedure A

A pyridine (500 mL) suspension of O-benzylhydroxylamine hydrochloride(3.2 g; 0.02 mol) and the corresponding diacid dichloride (0.04 mol) wasstirred at room temperature for three days. Water (10 mL) was added andstirring was continued overnight. The solvent was evaporated and solidresidue was purified by column chromatography on silica gel intetrahydrofuran-methanol. The diacid product was dissolved in methanol(100 mL) and 5% Pd-C (100 mg) was added. The reaction suspension wasshaken overnight under hydrogen pressure (.sup.˜ 50 psi). The catalystwas separated by filtration, solid residue was washed with hot methanol(5×50 ml). The combined methanolic filtrates were evaporated. The solidresidue was slurried in acetone and filtered. The yield was 10-20%.

General procedure B

A pyridine (500 ml) solution of O-benzylhydroxylamine (2.46 g; 0.02 mol)and the corresponding dicarboxylic acid monobenzyl ester monoacidchloride (0.04 mol) was stirred at room temperature overnight. Thesolvent was evaporated. The semisolid residue was dissolved inchloroform (300 mL) and extracted with 5% hydrochloric acid (2×50 mL),10% potassium hydroxide (3×100 mL), and water (2×100 mL). The organiclayer was dried over anhydrous magnesium sulfate and evaporated. Thesolid residue was purified by column chromatography on silica gel inethyl acetate. The tribenzyl product was dissolved in methanol (100 mL)and 5% Pd-C (100 mg) was added. The reaction suspension was shaken underhydrogen pressure (.sup.˜ 50 psi) at room temperature overnight. Thesolid was separated by filtration and washed with hot methanol (5×50mL). The combined methanol filtrates were evaporated to solid residue.The solid residue was slurried in cooled acetone and filtered. The yieldof target product was 30-60%. ##STR53##

¹ H NMR (DMSO-d₆, 200MHz), δ(ppm) 11.53 (s, COOH, 1H); 2.41 (t, J=7.2Hz, CH₂ CON(OH)COCH₂, 4H); 2.18 (t, J=7.0 Hz, CH₂ COOH, 4H); 1.52 (m, 8h); 1.22 (m, H). MS (FAB, glycerin) 346(M+1)

Compounds having the structure: ##STR54##

A pyridine (500 mL) solution of the monomethyl ester monoacid chlorideof dicarboxylic acid (0.02 mol) and N,N'-dimethyl-1,x-diaminoalkane(0.01 mol) was stirred at room temperature overnight. Solvent wasevaporated and oily residue was dissolved in chloroform (300 mL).Chloroform solution was washed with water (3×50 mL), 10% potassiumhydroxide (3×50 mL), 10% hydrochloric acid (3×50 mL), and again withwater (3×50 mL). The organic layer was dried and evaporated. The oilyresidue was dissolved in potassium hydroxide (1.2 g; 0.021 mol) in 80%methanol (100 mL). The reaction mixture was refluxed two hours. Thesolvent was evaporated and solid residue was dissolved in water (50 mL)and extracted with chloroform (3×50 mL). Water solution was acidified topH.sup.˜ 5 and concentrated (to volume of about 10 mL). The watersolution or suspension was cooled down and precipitate was separated byfiltration. The solid product was purified by crystallization from ethylacetate. The yield was 40-60%. ##STR55##

¹ H NMR (CDCl₃, 200 MHz), δ(ppm) 8.15 (s, broad, COOH, 2H); 3.52+3.45(2s, CH₂ N, 4H); 3.01+2.93 (2s, CH₃ N, 6H); 2.30 (4t, CH₂ CO, 8H); 1.60(m, 8H); 1.32 (m, 8H). ¹ H NMR (DMSO-d₆, 200 MHz), δ(ppm)3.44+3.336+3.36 (3s, CH₂ N, 4H); 2.94+2.90+2.79 (3s, CH₃ N, 6H);2.27+2.23+2.12 (3t, CH₂ CO, 8H); 1.46 (m, 8H); 1.23 (m, 8H).

Compounds having the structure: ##STR56##

A pyridine (500 mL) solution of 6-aminocapric acid (2.6 g; 0.02 mol) andterephthaloyl chloride (2 g; 0.01 mol) was stirred at room temperatureovernight (.sup.˜ 12 hours), and at 90° C. for 23 hours. The solvent wasevaporated, and the solid residue was crystallized from water (10 mL)four times. The yield was 800 mg (19%). ¹ H NMR (DMSO-d₆, 200 MH),δ(ppm) 12.8 (s, broad, COOH, 2H); 8.54+7.72 (2t, NH, 2H); 3.24+2.98 (2m, NHCH₂, 4H); 2.20+2.03 (2m, CH₂ CO, 4H); 1.50 (m, 8H); 1.32 (m, 4H).

Compound having the structure: ##STR57##

Into a mixture of aniline (2.75 g; 0.03 mol), hydroxylaminehydrochloride (2.08 g; 0.03 mol), and potassium hydroxide (5.50 g; 0.09mol) in 50% tetrahydrofuran (100 mL) was slowly added at roomtemperature a tetrahydrofuran (20 mL) solution of terephthaloyl chloride(6 g; 0.03 mol). The reaction suspension was stirred at room temperaturefor thirty minutes. The solvent was evaporated. The solid residue wasslurried in hot methanol (1000 mL) and dried over anhydrous magnesiumsulfate. The methanol solution was separated by filtration and filtratewas evaporated. The solid residue was slurried in 20 mL cooled methanoland filtered. The white crystals were washed with ether (5×50 mL) anddried. The yield was 4.6 g (39%). ¹ H NMR (DMSO-d₆, 200 MHz), δ(ppm)11.35 (s, broad, NHOH, 1H); 10.35 (s, NHPh, 1H); 9.19 (s, NHOH, 1H);8.03 (d, J=8 Hz, terephthalic protons, 2H); 7.89 (d, J=8 Hz,terephthalic protons, 2H); 7,82 (d, J=7.4 Hz, ortho anilide protons,2H); 7.34 (t, J=7.4 Hz, meta anilide protons, 2H); 7.10 (t, J=7.4 Hz,para anilide proton, 1H).

Compound having the structure: ##STR58##

A solution of 1,4-phenylenediacrylic acid (2.18 g; 0.01 mol) in thionylchloride (50 mL; 81.55 g; 0.68 mol) was refluxed overnight. The excessof thionyl chloride was evaporated. The solid was dissolved intetrahydrofuran (20 mL), and added to a cooled (0° C.) solution ofpotassium hydroxide (1.12 g; 0.02 mol) and aniline in 50%tetrahydrofuran. The reaction mixture was stirred at room temperaturefor thirty minutes. The solvent was evaporated. The solid residue wasslurried in water and filtered. White crystals were dissolved in a smallamount of methanol and purified on a silica gel column intetrahydrofuran. The yield was 315 mg (10%). ¹ H NMR (DMSO-d₆, 200 MHz),δ(ppm) 10.80 (s, NHOH, 1H); 10.23 (s, NHPh, 1H); 9.09 (s, NHOH, 1H);7.69 (d, J=7.6 Hz, ortho anilide protons, 2H); 7.64 (s, phenyleneprotons, 4H), 7.55 (d, J=15.8 Hz, PhNHOCCH═CH--, 1H); 7.40 (d, J=15.8Hz, HONHOCCH═CH--, 1H); 7.33 (t, J=7.8 Hz, meta anilide protons, 2H);7.06 (t, J=7.2 Hz, para anilide protons, 1H); 6.89 (d, J=15.8 Hz,PhNHOCCH═CH-- , 1H) 6.51 (d, J=15.8 Hz, HOHNOCCH═CH--, 1H ).

Compounds having the structure: ##STR59## wherein n=4, 5, 6, 7, and 8.

A chloroform solution of triethylamine (1.4 mL; 1.0 g; 0.01 mol), thecorresponding amine (0.01 mol) and diacid dichloride (0.005 mol) wasstirred at room temperature for five hours. If the reaction mixture wasclear, it was washed with water (5×100 mL). The organic layer was driedover anhydrous magnesium sulfate and evaporated to a solid residue. Ifin the course of reaction a precipitate was formed, the precipitate wasseparated by filtration. White crystals from filtration or solid residuefrom evaporation were crystallized from ethyl acetate, tetrahydrofuran,methanol, or their mixture. The yields were from 60-90%. ##STR60##

¹ H NMR (DMSO-d₆, 200 MHz), δ(ppm) 10.23 (s, NH, 2H); 7.82 (d, J=9 Hz,aromatic protons, 4H) , 7.60 (d, J=9 Hz, aromatic protons, 4H) , 2.31(t, J=7.4 Hz, CH₂ CO, 4H); 2.61 (m, 4H); 1.32 (m, 4H). ##STR61##

¹ H NMR (DMSO-d₆, 200 MHz), δ(ppm) 10.48 (s, NH, 2H); 8.18 (d, J=9.2 Hz,aromatic protons, 4H); 7.81 (d, J=9.2 Hz, aromatic protons, 4H0; 2.37(t, J=7.2 Hz, CH₂ CO--, 4H); 1.60 (m, 4H); 1.33 (m, 4H). ##STR62##

¹ H NMR (DMSO-d₆, 200 MHz), δ9.91 (s, NH, 2H), 7.58 (d, J=8.6 Hz,aromatic protons, 4H); 7.26 (d, J=8.6 Hz, aromatic protons, 4H); 3.94(s, CH₂ CN, 4H); 2.29 (t, J=7.4 Hz, CH₂ CO--, 4H); 1.60 (m, 4H); 1.31(m, 4H). ##STR63##

¹ H NMR (DMSO-d₆, 200 MHz), δ(ppm) 10.08 (s, CONHAr, 2H); 7.79 (d, J=8.6Hz, aromatic protons, 4H); 7.63 (d, J=8 Hz, aromatic protons, 4H), 7.22(s, H₃ CHNCO--, 2H); 3.32 (s, CH₃, 6H); 2.31 (t, J=7 Hz, CH₂ C--), 6H);1.59 (m, 4H); 1.31 (m, 4H). ##STR64##

¹ H NMR (DMSO-d₆, 200 MHz), δ(ppm) 10.90 (s, broad, NHOH, 2H); 10.05 (s,NHAr, 2H); 8.90 (s, broad, NHOH, 2H); 7.68 (d, J=9 Hz, aromatic protons,4H); 7.62 (d, J=9 Hz, aromatic protons, 4H); 2.31 (t, J=7.2 Hz, CH₂CO--, 4H); 1.59 (m, 4H); 1.30 (m, 4H). ##STR65##

¹ H NMR (DMSO-d₆, 200 MHz), δ(ppm) 10.06 (s, broad, NH, 2H); 8.71 (d,J=2.6 Hz, aromatic protons, 2H); 7.31 (d+d, aromatic protons, 2H); 2.32(t, J=7.4 Hz, CH₂ CO--, 4H); 1.59 (m, 4H); 1.33 (m, 4H). ##STR66##

¹ H NMR (DMSO-d₆, 200 MHz), δ(ppm) 12.00 (s, broad, NH, 2H); 7.43 (d,J=3.6 Hz, aromatic protons, 2H); 7.16 (d, J=3.6 Hz, aromatic protons,2H); 2.41 (t, J=7.2 Hz, CH₂ CONH--, 4H) 1.58 (m, 4H); 1.28 (m, 4H).

In the similar manner, the following compounds were prepared andcharacterized: ##STR67## wherein n=4, 5, 6, 7, and 8; all compounds aresymmetrical wherein R is 2-, 3-, and 4-cyano; 2-, 3-, and 4-methylcyano;2-, 3-, and 4-nitro, 2-, 3-, and 4-carboxy; 2-, 3-, and 4-aminocarbonyl;2-, 3-and 4-methylaminocarbonyl; 2-, 3-, and 4-dimethylaminocarbonyl;and 2-, 3-, and 4-trifluoromethyl; ##STR68## wherein R is4-hydroxylaminocarbonyl; 4-methoxycarbonyl; 2-, 3-, and 4-chloro; 2-,3-, and 4-fluoro; 2-, 3-, and 4-methyl; 2-, 3-, and 4-methoxy;2,3-difluoro; 2,4-difluoro; 2,5-difluoro; 2,6-difluoro;1,2,3,-trifluoro, 3,4,5-trifluoro; 2,3,5,6-tetrafluoro;2,3,4,5,6-pentafluoro. ##STR69## Compounds having the structure:##STR70## wherein n=4, 5, 6, 7, and 8.

General procedure A

A diacid dichloride (0.01 mol) was added to a stirred solution ofpotassium hydroxide (1.68 g; 0.03 mol), hydroxylamine hydrochloride (0.7g; 0.01 mol), and the corresponding aniline (0.01 mol) in 50%tetrahydrofuran (100 mL). The resulting reaction mixture was stirred atroom temperature thirty minutes, and solvent was evaporated to solidresidue. The solid residue was slurried in methanol (.sup.˜ 100 mL) anddried over anhydrous magnesium sulfate. The methanol solution wasseparated by filtration and evaporated to a solid residue. The productwas purified by column chromatography on silica gel in ethylacetate-tetrahydrofuran (in most cases 3:1). The yields were 15-30%.

General procedure B

A solution of corresponding monomethyl ester of dicarboxylic acid (0.01mol), oxaloyl chloride (0.03 mol), and a few drops DMF in benzene (500mL) was stirred at room temperature overnight. The solvent wasevaporated and the oily residue was dissolved in dry benzene (3×50 mL)and evaporated again. The tetrahydrofuran (50 mL) solution of monoestermonoacid chloride of the corresponding dicarboxylic acid was slowlyadded to a cooled solution of the corresponding amine (0.01 mol) andpyridine (1.6 mL; 1.6 g; 0.02 mol) in tetrahydrofuran (200 mL). Thereaction mixture was stirred at room temperature for an hour. Thesolvent was evaporated, the reside was dissolved in chloroform (300 mL),and the chloroform solution was washed with 10% hydrochloric acid (3×50mL), 10% potassium hydroxide (3×50 mL), and water (3×50 mL). The organiclayer was dried over anhydrous magnesium sulfate and evaporated,yielding the pure monoester monoamide of dicarboxylic acid. The productwas dissolved in 80% methanol with potassium hydroxide (0.56 g; 0.01mol). The reaction mixture was refluxed two hours and evaporated tosolid residue. The residue was dissolved in water (.sup.˜ 20 mL) andacidified to .sup.˜ pH 5 with 10% hydrochloric acid. The monoacidmonoamide of the dicarboxylic acid was isolated by filtration ofprecipitate or extraction water solution with chloroform. The isolatedmonoacid monoamide of the dicarboxylic acid was mixed together with anequivalent amount of O-benzylhydroxylamine and1,3-dicyclohexylcarbodiimide in pyridine (.sup.˜ 100 mL per 0.01 mol ofO-benzylhydroxylamine) and was stirred at room temperature overnight.The solvent was evaporated and the solid residue was partitioned betweenchloroform (500 mL) and 10% hydrochloric acid (300 mL). The organiclayer was washed with water (3×100 mL) and dried over anhydrousmagnesium sulfate. The solvent was evaporated to solid residue. Thesolid residue was dissolved in large amounts of tetrahydrofuran andfiltered through a short column of silica gel. The crude product wasdissolved in methanol (100 mL) and 5% Pd-C was added. The reactionsuspension was shaken under hydrogen pressure (.sup.˜ 50 psi) overnight.The catalyst was separated by filtration and filtrate was evaporated tosolid residue. The solid residue was slurried in hexanes and filtered.Mostly pure product was isolated in this way. If necessary furtherpurification was achieved by column chromatography on silica gel withethyl acetate-tetrahydrofuran. The yields were from 35% to 65%.

General procedure C

A pyridine (500 mL solution of O-benxylhyroxylamine (1.23; 0.01 mol),the corresponding amine (0.01 mol), and the dichloride of thedicarboxylic acid (0.01 mol) was stirred at room temperature overnight.The solvent was evaporated and the white solid residue contains, judgedby ¹ H NMR, two symmetrical amides and a target unsymmetrical one. Thesolid residue was slurried in methanol and dried over anhydrousmagnesium sulfate. The filtrate was evaporated and the solid residue wasdissolved in methanol (.sup.˜ 100 mL). Into the methanol solution 5%Pd-C (100 mg) was added and the black suspension was shaken underhydrogen pressure (.sup.˜ 50 psi) overnight. The catalyst was separatedby filtration and the filtrate was evaporated. The product was isolatedby column chromatography on silica with ethyl acetate-tetrahydrofuran.The yields were from 20% to 35%.

General procedure D

A chloroform solution of triethylamine (3 mL; 2.18 g; 0.0215 mol), thecorresponding amine (0.01 mol), O-trimethylsilyl)hydroxylamine (1.05 g,0.01 mol), and the corresponding diacid chloride of the dicarboxylicacid (0.01 mol) was stirred at room temperature overnight. The solventwas evaporated, the residue was dissolved in methanol (.sup.˜ 10 mL),and into the methanol solution 10% ammonium chloride (.sup.˜ 10 mL) wasadded. The resulting suspension was stirred at 50° C. for two hours. Thesolvent was evaporated. The solid residue was slurried in methanol (300mL) and dried over anhydrous magnesium sulfate. The methanol solutionwas separated by filtration and evaporated to a solid residue. Theproduct was isolated by silica gel column chromatography with ethylacetate-tetrahydrofuran. The yields were 20-33%.

    ______________________________________                                         ##STR71##                                                                                     C       H      N                                             ______________________________________                                        Elemental analysis:                                                                          Calc.   63.62     7.63 10.60                                                  Found   63.58     7.59 10.48                                   ______________________________________                                    

¹ H NMR (DMSO-d₆, 200 MHz), δ(ppm) 10.31 (s, NHOH, 1H); 9.83 (s, NHPh,1H); 8.64 (s, NHOH, 1H); 7.57 (d, J=8.2 Hz, ortho aromatic protons, 2H);7.26 (t, J=8.4 Hz, meta aromatic protons, 2H), 6.99 (t, J=7.4 Hz, paraaromatic protons, 1H); 2.27 (t, J=7.4 Hz, CH₂ CONHPh, 2H); 1.93 (t,J=7.2 Hz, CH₂ CONHOH, 2H); 1.52 (m, 4H); 1.26 (m, 4H). MS (Fab,Glycerin) 172, 204, 232, 249, 265, (100%, M+1). ##STR72##

¹ H NMR (DMSO-d₆, 200 MHz), δ(ppm) 10.31 (s, NHOH, 1H); 10.08 (s, NHPh,1H); 8.64 (s, NHOH, 1H); 7.78 (d, J=7.6 Hz, aromatic protons, 1H); 7.66(t, J=7.4 Hz, aromatic protons, 1H); 7.48 (d, J=7.8 Hz, aromaticprotons, 1H); 7.29 (t, J=7.4 Hz, aromatic protons, 1H); 2.34 (t, J=7 Hz,CH₂ CONHAr, 2H); 1.93 (t, J=7.4 Hz, CH₂ CONHOH, 2H); 1.58 (m, 4H); 1.27(m, 4H). ##STR73##

¹ H NMR (DMSO-d₆, 200 MHz), δ(ppm) 10.31 (s, NHOH, 1H); 10.21 (s, NHPh,1H); 8.65 (s, NHOH, 1H); 8.09 (s, aromatic proton, 1H); 7.77 (m,aromatic proton, 1H); 7.49 (m, aromatic proton, 1H); 2.31 (t, J=7.2 Hz,CH₂ CONHAr, 2H); 1.93 (t, J=7.2 Hz, CH₂ CONHOH, 2H); 1.51 (m, 4H).##STR74##

¹ H NMR (DMSO-d₆, 200 MHz), δ(ppm) 10.35 (s, NHAr, 1H); 10.31 (s, NHOH,1H); 8.63 (s, NHOH+aromatic proton 2H); 7.88 (d, J=8 Hz, aromaticprotons, 2H); 7.57 (t, J=8 Hz, aromatic proton, 1H); 2.33 (t, J=7.6 Hz,CH₂ CONHAr, 2H); 1.93 (t, J=7.4 Hz, CH₂ CONHOH, 2H), 1.52 (m, 4H); 1.27(m, 4H). ##STR75##

¹ H NMR (DMSO-d₆, 200 MHz), δ(ppm) 10.33 (s, NHOH, 1H); 10.15 (s, NHAr,1H); 10.09 (s, NHPh, 1H); 8.66 (s, NHOH, 1H); 7.91 (d, J=8.6 Hz,aromatic protons, 2H); 7.76 (d, J=7.8 Hz, ortho aniline protons, 2H);7.71 (d, J=8.6 Hz, aromatic protons, 2H); 7.33 (t, J=7.6 Hz, metaanilide protons, 2H); 7.07 (t, J=7.4 Hz, para anilide protons); 2.33 (t,J=7.5 Hz, CH₂ NHAr, 2H); 1.93 (t, J=7.2 Hz, CH₂ CNHH, 2H); 1.51 (m, 4H);1.28 (m, 4H). ##STR76##

¹ H NMR (DMSO-d₆, 200 MHz), δ(ppm) 10.32 (s, NHOH, 1H); 10.21 (s, NHAr,1H); 8.65 (s, NHOH, 1H); 7.31 (d of d, J=10 Hz(2.2 Hz), aromaticprotons, 2H); 6.84 (t of t, J=9.4 Hz(2.4Hz), aromatic protons, 1H); 2.29(t, CH₂ CONHAr, 2H); 1.93 (t, J=7.2 Hz, CH₂ CONHOH, 2H); 1.51 (m, 4H);1.26 (m, 4H).

In the same manner the following compounds were prepared andcharacterized: ##STR77## wherein n=4, 5, 6, 7, and 8; and R is 2-, 3-,and 4-cyano; 2-, 3-, and 4-methylcyano; 2-, 3-, and 4-nitro; 2-, 3-, and4-carboxy; 2-, 3-, and 4-aminocarbonyl; 2-, 3-, and4-methylaminocarbonyl; 2-, 3-, and 4-dimethylaminocarbonyl; and 2-, 3-,and 4-trifluoromethyl; ##STR78## wherein R is 4-hydroxylaminocarbonyl;4-methoxycarbonyl; 4-tetrazoyl; 2-, 3-, and 4-chloro; 2-, 3-, and4-fluoro; 2-, 3-, and 4-methyl; 2-, 3-, and 4-methoxy; 2,3-difluoro;2,4-difluoro; 2,5-difluoro; 2,6-difluoro; 1,2,3-trifluoro;3,4,5-trifluoro; 2,4,5-trifluoro; 2,4,6-trifluoro; 2,3,6-trifluoro;2,3,5,6-tetrafluoro; 2,3,4,5,6-pentafluoro; 2-, 3-, and 4-phenyl; 2-,3-, and 4-benzyloxy; 4-hexyl; and 4-t-butyl; ##STR79## Compounds havingthe structure: ##STR80## wherein n=4, 5, 6, 7, and 8; and R is hydrogenor methyl.

A diacid dichloride (0.01 mol) was added into a stirred solution ofpotassium hydroxide (1.68 g; 0.03 mol), aniline or N-methylaniline (0.01mol), and dimethylamine hydrochloride (0.805 g; 0.01 mol) in 50%tetrahydrofuran (100 mL). The reaction mixture was stirred thirtyminutes at room temperature. The solvent was partitioned betweenchloroform (400 mL) and water (300 mL). The organic layer was washedwith 10% hydrochloric acid (3×100 mL), 10% potassium hydroxide (3×100mL), and water (2×100 mL). The organic layer was dried over anhydrousmagnesium sulfate and evaporated. The solid residue was slurried inhexanes and filtered. The yield were 25-34%. ##STR81##

¹ H NMR (DMSO-d₆, 200 MHz), δ(ppm) 9.82 (s, NHPh, 1H); 7.58 (d, J=7.6Hz, ortho aromatic protons, 2H); 7.26 (t, J=7.4 Hz, meta aromaticprotons, 2H); 6.99 (t, J=7.4 Hz, para aromatic proton, 1H); 2.85 (d,J=28 Hz, N(CH₃)₂, 6H); 2.28 (t, J=7.2 Hz, CH₂ CO, 2H); 2.24 (t, J=7.4Hz, CH₂ CO, 2H); 1.51 (m, 4H); 1.29 (m, 4H). ##STR82##

¹ H NMR (DMSO-d₆, 200 MHz), δ(ppm) 7.30 (m, C₆ H₅, 5H); 3.13 (s, H₃CNPh, 3H); 2.83 (d, J=26 Hz, N(CH₃)₂, 6H); 2.17 (t, J=7.6 Hz, CH₂CON(CH₃)₂, 2H); 1.98 (t, J=7.4 Hz, CH₂ CON(CH₃)Ph, 2H); 1.41 (m, 4H);1.11 (m, 4H).

                                      TABLE 1                                     __________________________________________________________________________                                               Benzidine                                                          Mol.                                                                              Optimal                                                                              Reactive                           CPD                                                                              Structure                    Weight                                                                            Conc. (μM)                                                                        Cells (%)                          __________________________________________________________________________        ##STR83##                                                                 1  n = 4 (known compound)       236 80     70                                 2  n = 5                        250 20     84                                 3  n = 6                        264 2.5    70                                 4  n = 7                        278 20      8                                 5  n = 8                        292 20     15                                     ##STR84##                   274 31     44                                 7                                                                                 ##STR85##                   274 31     52                                 8                                                                                 ##STR86##                   294 12.5   32                                 9                                                                                 ##STR87##                   225 50     20                                 10                                                                                ##STR88##                   355 250    26                                 11                                                                                ##STR89##                   216 60     53                                 12                                                                                ##STR90##                   189 250    35                                 13                                                                                ##STR91##                   203 60     17                                 14                                                                                ##STR92##                   156 125    30                                 15                                                                                ##STR93##                   218 20     43                                 16                                                                                ##STR94##                   270  8     35                                 17                                                                                ##STR95##                   256 62     30                                 18                                                                                ##STR96##                   260 31     38                                 19                                                                                ##STR97##                   278  5     24                                     ##STR98##                                                                 20 R = 4-methyl                 273 20     52                                 21 R = 4-cyano                  289  7     70                                 22 R = 3-cyano                  289  5     55                                 23 R = 2-cyano                  289 16     65                                 24 R = 3-nitro                  309  5     30                                 25 R = 4-nitro                  309 0.8    30                                 26 R = 3-trifluoromethyl        332 30     30                                 27 R = 4-trifluoromethyl        332  5     47                                 28 R = 2-amino                  279 20     54                                 29 R = 4-cyanomethyl            303  1     30                                 30 R = 3-chloro                   298.5                                                                            2     33                                 31 R = 4-azido (N.sub.3)        304  2     47                                 32 R = 2-fluoro                 282  4     65                                 33 R = 3-fluoro                 282  1     25                                 34 R = 4-fluoro                 282  4     43                                 35 R = 4-benzyloxy              370  4     20                                 36 R = 4-methyoxycarbonyl       322  4     28                                 37 R = 4-methylaminocarbonyl    321 30     16                                 38 R = 2-bromo                  343  8     45                                 39 R = 2-chloro                   298.5                                                                            4     34                                 40 R = 4-bromo                  343 1.6    47                                 41 R = 2,3-difluoro             300  8     24                                 42 R = 2,4,5-trifluoro          318  8     36                                 43 R = 2,3,6-trifluoro          318 31     53                                 44 R = 2,4,6-trifluoro          318 16     47                                 45 R = 2,4-difluoro             300  6     60                                 46 R = 2,3,4,5,6-pentafluoro    354 31     53                                 47 R = 3,4-difluoro             300  4     61                                 48 R = 3,4,5-trifluoro          318  8     55                                 49 R = 2,5-difluoro             300  4     70                                 50 R = 3,5-difluoro             300  2     73                                 51 R = 2-methoxy                294  8     36                                 52 R = 3-methoxy                294  6     38                                 53 R = 4-methoxy                294  6     37                                 54                                                                                ##STR99##                   290 20     40                                 55                                                                                ##STR100##                  256 30     53                                     ##STR101##                                                                56 R = 4-trifluoromethyl        460 50     20                                 57 R = 4(N)-hydroxylaminocarbonyl                                                                             442  8     10                                 58 R = 4-cyanomethyl            402 50     25                                 59 R = 2,4-difluoro             396 500    54                                 60 R = 2,6-difluoro             396 100    21                                 61 R = 3,5-difluoro             396 125    31                                 62 R = 2,3,6-trifluoro          432 250    28                                 63 R = 2,4,6-trifluoro          432 125    35                                 64 R = 2,3,4,5,6-pentafluoro    504 125    13                                 65 R = 4-nitro                  414 25     14                                 66                                                                                ##STR102##                  270 1250   80                                 67                                                                                ##STR103##                  256 2500   90                                 68                                                                                ##STR104##                  204 125    56                                 69                                                                                ##STR105##                  333 60     40                                 70                                                                                ##STR106##                  226 160    19                                     ##STR107##                                                                71 n = 4                        310 100     8                                 72 n = 5                        324 250    10                                 73 n = 6                        338 50      7                                 74 n = 7                        352 100    10                                 75 n = 8                        366 100    10                                 __________________________________________________________________________

                  TABLE 2                                                         ______________________________________                                        Induction of Differentiation of HL-60                                                Mol.         Optimal   NBT                                             CPD    Weight       Conc.(μM)                                                                            Positive (%)                                    ______________________________________                                         2     250          7         22                                               3     264          1         21                                               6     274          20        30                                               7     274          20        21                                              22     289          1.7       28                                              21     289          2          6                                              26     332          6         27                                              25     309          3         18                                              36     322          1         32                                              31     304          2.5        7                                              29     303          1         15                                              43     318          2         20                                              ______________________________________                                    

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What is claimed is:
 1. A compound having the structure: ##STR108## wherein each of R₁ and R₂ are independently the same as or different from each other; when R₁ and R₂ are the same, each is a substituted or unsubstituted cycloalkylamino, pyridineamino, piperidino, 9-purine-6-amine, or thiazoleamino group; when R₁ and R₂ are different, R₁ =R₃ --N--R₄, wherein each of R₃ and R₄ are independently the same as or different from each other and are a hydrogen atom, a hydroxyl group, a substituted or unsubstituted, branched or unbranched alkyl, alkenyl, cycloalkyl, aryl, alkyloxy, aryloxy, arylalkyloxy, or pyridine group, or R₃ and R₄ bond together to form a piperidine group and R₂ is a hydroxylamino, hydroxyl, amino, alkylamino, or alkyloxy group; and n is an integer from about 4 to about
 8. 2. A compound of claim 1 having the structure: ##STR109## wherein each of R₃ and R₄ are independently the same as or different from each other and are a hydrogen atom, a hydroxyl group, a substituted or unsubstituted, branched or unbranched alkyl, alkenyl, cycloalkyl, aryl, alkyloxy, aryloxy, arylalkyloxy, or pyridine group, or R₃ and R₄ bond together to form a piperidine group; R₂ is a hydroxylamino, hydroxyl, amino, alkylamino, or alkyloxy group; and n is an integer from about 4 to about
 8. 3. A compound of claim 2, wherein R₂ is a hydroxylamino, hydroxyl, amino, methylamino, or methyoxy group and n is
 6. 4. A compound of claim 3, wherein R₄ is a hydrogen atom and R₃ is a substituted or unsubstituted phenyl group.
 5. A compound of claim 4, wherein the phenyl group is substituted with a methyl, cyano, nitro, trifluoromethyl, amino, aminocarbonyl, methylcyano, chloro, fluoro, bromo, iodo, 2,3-difluoro, 2,4-difluoro, 2,5-difluoro, 3,4-difluoro, 3,5-difluoro, 2,6-difluoro, 1,2,3-trifluoro, 2,3,6-trifluoro, 2,4,6-trifluoro, 3,4,5-trifluoro, 2,3,5,6-tetrafluoro, 2,3,4,5,6-pentafluoro, azido, hexyl, t-butyl, phenyl, carboxyl, hydroxyl, methyoxy, phenyloxy, benzyloxy, phenylaminooxy, phenylaminocarbonyl, methyoxycarbonyl, methylaminocarbonyl, dimethylamino, dimethylaminocarbonyl, or hydroxylaminocarbonyl group.
 6. A compound of claim 3, wherein R₄ is a hydrogen atom and R₃ is a cyclohexyl group.
 7. A compound of claim 3, wherein R₄ is a hydrogen atom and R₃ is a methyoxy group.
 8. A compound of claim 3, wherein R₃ and R₄ bond together to form a piperidine group.
 9. A compound of claim 3, wherein R₄ is a hydrogen atom and R₃ is a hydroxyl group.
 10. A compound of claim 3, wherein R₄ is a hydrogen atom and R₃ is a benzyloxy group.
 11. A compound of claim 3, wherein R₄ is a hydrogen atom and R₃ is a δ-pyridine group.
 12. A compound of claim 3, wherein R₄ is a hydrogen atom and R₃ is a β-pyridine group.
 13. A compound of claim 3, wherein R₄ is a hydrogen atom and R₃ is a α-pyridine group.
 14. A compound of claim 3, wherein R₃ and R₄ are both methyl groups.
 15. A compound of claim 3, wherein R₄ is a methyl group and R₃ is a phenyl group.
 16. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of the compound of claim
 2. 17. A pharmaceutical composition of claim 16 in combination with an antitumor agent. 